Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects

Alzheimer Dis Assoc Disord. 2013 Jul-Sep;27(3):278-86. doi: 10.1097/WAD.0b013e3182622ace.


CHF5074 has been shown to inhibit brain β-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclopropanes / adverse effects
  • Cyclopropanes / blood
  • Cyclopropanes / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Flurbiprofen / adverse effects
  • Flurbiprofen / analogs & derivatives*
  • Flurbiprofen / blood
  • Flurbiprofen / pharmacokinetics
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / blood
  • Neuroprotective Agents / pharmacokinetics*
  • Young Adult


  • 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid
  • Cyclopropanes
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Flurbiprofen